Abstract
Abstract TAM receptors (Tyro-3, Axl, Mer) are a family of three homologous receptor tyrosine kinases that play a role in the phagocytosis of apoptotic cells (a process termed efferocytosis in recent years). TAM receptors on the surface of epithelial cells bind to soluble ligands Gas6 and Protein S, which in turn, bind to phosphatidylserine-expressing apoptotic cells. After epithelial cells phagocytose apoptotic cells, they release anti-inflammatory cytokines (e.g. IL-10, TGFβ) to attenuate the immune response. This non-canonical role of TAM receptors as efferocytosis receptors is in addition to their well-studied canonical role as tyrosine kinase receptors that activate cell proliferation signaling pathways (e.g. PI3K, Ras, ERK). Therefore, overexpression of TAM receptors on cancer cells has a dual effect on tumor progression. To date, TAM receptors have been implicated in numerous cancers, including breast cancer; and various family members have been shown to be overexpressed in mouse and human mammary tumor cells. We propose that efferocytosis is a unique and novel oncogenic event by virtue of its role in the production of immunosuppressing factors into the tumor microenvironment. To study this, we set up a unique 3D acini model, where luminal apoptotic cells are engulfed by the basal cells of the acini. Using this system along with 2D cultures, we demonstrated that overexpression of Mer increased the rate of efferocytosis, but does not act as a classical oncogene by filling in the luminal space. Additional studies such as time-lapse studies of acini stained with caspases showed that Mer increased the rate of clearance. This adapted method offers a unique system to study cancer cell efferocytosis, and the role of TAM receptors in cancer progression and immune evasion. Citation Format: Shelly Hsieh, Khanh Q. Nguyen, Stanley Kimani, Raymond B. Birge. Non-canonical role of TAM receptors in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 143. doi:10.1158/1538-7445.AM2014-143
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